Novel heteroaryl peptidomimetics as thrombin receptor antagonists

ABSTRACT

The invention is directed to novel heteroaryl peptidomimetic compounds which are useful as thrombin receptor antagonists for the treatment of diseases associated with thrombosis, restenosis, hypertension, heart failure, arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions, angiogenesis and related disorders, cancer, and neurodegenerative disorders. Pharmaceutical compositions comprising the substituted heteroaryl peptidomimetics of the present invention and methods of treating conditions mediated by the thrombin receptor are also disclosed.

[0001] This application claims benefit from provisional patentapplication 60/436,130 filed on Dec. 23, 2002, which is herebyincorporated by reference herein.

FIELD OF THE INVENTION

[0002] This invention relates to certain novel thrombin receptorantagonists, their synthesis and their use for the treatment of diseasesassociated with thrombosis, restenosis, hypertension, heart failure,arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemicconditions, angiogenesis and related disorders, cancer, andneurodegenerative disorders.

BACKGROUND OF THE INVENTION

[0003] Thrombin is an important serine protease in hemostasis andthrombosis. One of the key actions of thrombin is cellular modulationvia receptor activation. A functional human thrombin receptor (PAR-1),cloned by Coughlin in 1991 (T. -K. Vu, Cell 1991, 64, 1057), was foundto be a member of the G-protein coupled receptor (GPCR) superfamily. Thereceptor activation putatively occurs by N-terminal recognition andproteolytic cleavage at the Arg-41/Ser-42 peptide bond to reveal atruncated N-terminus. This new receptor sequence, which has an SFLLRN(Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting as a tethered ligand torecognize a site on the receptor, can trigger activation and signaltransduction leading to platelet aggregation. Since 1991, three otherprotease-activated receptors with extensive homology to the thrombinreceptor, “PAR-2” (S. Nystedt, Proc. Natl. Acad. Sci USA 1994, 91,9208), “PAR-3” (H. Ishihara, Nature 1997, 386, 502), and “PAR-4” (W. -F.Xu, Proc. Natl. Acad. Sci USA 1998, 95, 6642), have been cloned.Thrombin receptor (PAR-1) specific antibody-induced blockade of theplatelet thrombin receptor has shown efficacy against arterialthrombosis in vivo (J. J. Cook Circulation 1995, 91, 2961). Hence,antagonists of the thrombin receptor (PAR-1) are useful to block theseprotease-activated receptors and, as such, may be used to treat plateletmediated thrombotic disorders such as myocardial infarction, stroke,restenosis, angina, atherosclerosis, and ischemic conditions.

[0004] The thrombin receptor (PAR-1) has also been identified on othercell types: endothelial, fibroblast, renal, osteosarcoma, smooth muscle,myocytes, tumor, and neuronal/glia. Thrombin activation of endothelialcells upregulates P-selectin to induce polymorphonuclear leukocyteadhesion—an inflammatory response of the vessel wall (Y. Sugama, J. CellBiol. 1992, 119, 935). In fibroblasts, thrombin receptor (PAR-1)activation induces proliferation and transmission of mitogenic signals(D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicatedin osteoblast proliferation through its activation of osteoblast cells(D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174, 181). Thrombinhas been implicated in the regulation and retraction of neurons (K.Jalink, J. Cell. Biol. 1992, 118, 411). Therefore, in this context, theantagonist compounds of this invention may also be useful againstinflammation, osteoporosis, angiogenesis and related disorders, cancer,neurodegenerative disorders, hypertension, heart failure, arrhythmia,glomerulonephritis.

[0005] In International Patent Application WO 01/00576, indole andindazole urea peptoids are disclosed as thrombin receptor antagonists.The general structure of the compounds disclosed is:

[0006] In International Patent Application WO 01/00656, novel indazolepeptidomimetic compounds are disclosed as thrombin receptor antagonists.The general structure of the compounds disclosed is:

[0007] In International Patent Application WO 01/00657, novel indolepeptidomimetic compounds are disclosed as thrombin receptor antagonists.The general structure of the compounds disclosed is:

[0008] In International Patent Application WO 01/00659, novelbenzimidazolone peptidomimetic compounds are disclosed as thrombinreceptor antagonists. The general structure of the compounds disclosedis:

[0009] The indole-based petide mimetics disclosed in the aboveinternational applications are also described in Zhang, H -C et. al.Bioorg. Med. Chem. Lett. 2001, 11, 2105-2109.

[0010] Similarly, the indole and indazole based compounds disclosed inthe above international applications are also described as thrombinreceptor antagonists in Zhang, H -C et. al. J. Med. Chem. 2001, 44,1021-1024.

[0011] The compounds of the present invention are a structurally novelclass of heteroaryl peptidomimetics represented by the general formula(I) below.

SUMMARY OF THE INVENTION

[0012] The present invention is directed to structurally novel compoundsrepresented by the following general formula (I):

[0013] wherein

[0014] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0015] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, and heteroaryl(C₁-C₈)alkylaminocarbonyl,diheteroaryl(C₁-C₈)alkylaminocarbonyl wherein said aryl, ar(C₁-C₈)alkyl,heteroaryl and heteroaryl(C₁-C₈)alkyl are optionally substituted withone or more of halogen, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, cyano, amino,and nitro; R₁ and R₂ are covalently bonded to the N-terminus of A₃ whenp is 1 or A₂ when p is 0;

[0016] Preferably R₁ is hydrogen;

[0017] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl;

[0018] R₃ is selected from hydrogen or C₁-C₈ alkyl; preferably, R₃ ishydrogen;

[0019] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃-C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0020] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0021] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0022] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0023] X is N or C;

[0024] Y is N, C or —CO—;

[0025] Provided that when Y is N, then X is C and there is a double bondbetween X and Y; Provided also that when Y is C, then X is C and thereis a double bond between X and Y; And provided also that when Y is —CO—,then X is N and there is a single bond between X and Y;

[0026] m is an integer selected from 0, 1, 2 or 3;

[0027] n is an integer selected from 1 or 2;

[0028] p is an integer selected from 0 or 1; preferably, p is 0;

[0029] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0030] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0031] A preferred embodiment of the present invention is directed tostructurally novel compounds represented by the following generalformula (II):

[0032] wherein

[0033] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0034] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0035] Preferably, R₁ is hydrogen;

[0036] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl;

[0037] R₃ is selected from hydrogen or C₁-C₈alkyl; preferably, R₃ ishydrogen;

[0038] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0039] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0040] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0041] Preferably, R₅ is selected from amino, C₁-C₆alkylamino,C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆dialkylamino;

[0042] m is an integer selected from 0, 1, 2 or 3;

[0043] n is an integer selected from 1 or 2;

[0044] p is an integer selected from 0 or 1; preferably, p is 0;

[0045] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0046] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0047] Another preferred embodiment of the present invention is directedto structurally novel compounds represented by the following generalformula (III):

[0048] wherein

[0049] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0050] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0051] Preferably, R₁ is hydrogen;

[0052] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl;

[0053] R₃ is selected from hydrogen or C₁-C₈ alkyl; preferably, R₃ ishydrogen;

[0054] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0055] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0056] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0057] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0058] m is an integer selected from 0, 1, 2 or 3;

[0059] n is an integer selected from 1 or 2;

[0060] p is an integer selected from 0 or 1; preferably, p is 0;

[0061] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0062] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0063] Still another preferred embodiment of the present invention isdirected to structurally novel compounds represented by the followinggeneral formula (IV):

[0064] wherein

[0065] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0066] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0067] Preferably, R₁ is hydrogen;

[0068] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl;

[0069] R₃ is selected from hydrogen or C₁-C₈alkyl; preferably, R₃ ishydrogen;

[0070] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0071] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0072] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0073] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0074] m is an integer selected from 0, 1, 2 or 3;

[0075] n is an integer selected from 1 or 2;

[0076] p is an integer selected from 0 or 1; preferably, p is 0;

[0077] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0078] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0079] Illustrative of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. Illustrating the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. An illustration of theinvention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier.

[0080] An example of the invention is a method of treating a disorder(preferably, a platelet-mediated thrombotic disorder) selected fromarterial and/or venous thrombosis, acute myocardial infarction,reocclusion following thrombolytic therapy and/or angioplasty,inflammation, unstable angina, stroke, restenosis, atherosclerosis,ischemic conditions, hypertension, heart failure, arrhythmia,glomerulonephritis, osteoporosis, angiogenesis and related disorders,cancer, neurodegenerative disorders and a variety of vaso-occlusivedisorders in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. In a preferred embodiment,the therapeutically effective amount of the compound is from about 0.1mg/kg/day to about 300 mg/kg/day.

[0081] Also included in the invention is the use of any of the compoundsdescribed above for the preparation of a medicament for a disorder(preferably, a platelet-mediated thrombotic disorder) selected fromarterial and/or venous thrombosis, acute myocardial infarction,reocclusion following thrombolytic therapy and/or angioplasty,inflammation, unstable angina, stroke, restenosis, atherosclerosis,ischemic conditions, hypertension, heart failure, arrhythmia,glomerulonephritis, osteoporosis, angiogenesis and related disorders,cancer, neurodegenerative disorders or a variety of vaso-occlusivedisorders in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0082] The present invention is directed to structurally novel compoundsrepresented by the following general formula (I):

[0083] wherein

[0084] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0085] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0086] Preferably R₁ is hydrogen;

[0087] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl;

[0088] R₃ is selected from hydrogen or C₁-C₈ alkyl; preferably, R₃ ishydrogen;

[0089] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0090] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where the substituentson the aryl, aralkyl, cycloalkyl or heteroaryl group are independentlyselected from one to three substituents selected from halogen, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl, fluorinated C₁-C₄alkyl,fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0091] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0092] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0093] X is N or C;

[0094] Y is N, C or —CO—;

[0095] Provided that when Y is N, then X is C and there is a double bondbetween X and Y; Provided also that when Y is C, then X is C and thereis a double bond between X and Y; And provided also that when Y is —CO—,then X is N and there is a single bond between X and Y;

[0096] m is an integer selected from 0, 1, 2 or 3;

[0097] n is an integer selected from 1 or 2;

[0098] p is an integer selected from 0 or 1; preferably, p is 0;

[0099] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0100] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0101] Preferred compounds of formula (I) are those wherein

[0102] (1) A₁ is an unsubstituted or substituted amino acid residueselected from the group consisting of phenylalanine, cyclohexylalanine,alanine, β-alanine, heteroarylalanine, naphthylalanine,homophenylalanine, arylglycine, heteroarylglycine, aryl-β-alanine, andheteroaryl-β-alanine wherein the substituents on the amino acid areindependently selected from one or more of halogen, C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino, guanidino,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄alkylsulfonyl,C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄alkenyl, alkynyl, or nitro;

[0103] (2) more preferably, A₁ is an unsubstituted or substituted aminoacid residue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine, wherein the substituents onthe amino acid are independently selected from one or more of halogen,C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0104] (3) even more preferably, A₁ is an unsubstituted amino acidresidue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine;

[0105] (4) most preferably, A₁ is phenylalanine or cyclohexylalanine;

[0106] (5) A₂ is an amino acid selected from the group consisting ofarginine, homoarginine, 2,4-diaminobutyric acid (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), 2,3diaminopropionic acid (optionally substituted with acyl, C₁-C₄alkyl,aroyl, amidino, or MeC(NH)—), glutamine, and lysine (optionallysubstituted with acyl, C₁-C₄alkyl, aroyl, amidino or MeC(NH)—);

[0107] (6) preferably, A₂ is an amino acid selected from the groupconsisting of arginine, homoarginine, 2,4-diaminobutyric acid,2,3-diaminopropionic acid, glutamine, and lysine;

[0108] (7) more preferably, A₂ is arginine;

[0109] (8) R₁ is hydrogen;

[0110] (9) R₂ is selected from hydrogen, C₁-C₈alkyl, aryloxycarbonyl,C₁-C₈alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0111] (10) more preferably, R₂ is selected from C₁-C₈alkylcarbonyl,aryloxycarbonyl, arylaminocarbonyl, and ar(C₁-C₈alkoxy)carbonyl, whereinsaid aryl, ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl areoptionally substituted with one or more of halogen, C₁-C₈alkyl, andC₁-C₈alkoxy;

[0112] (11) most preferably, R₂ is selected from acetyl, Fmoc, andp-methoxyphenylaminocarbonyl;

[0113] (12) R₃ is hydrogen;

[0114] (13) R₄ is substituted aryl, where the substituents on the arylare independently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0115] (14) more preferably, R₄ is substituted aryl, where thesubstituents on the aryl are one to three halogen substituents;

[0116] (15) most preferably, R₄ is 4-fluorophenyl;

[0117] (16) R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0118] (17) preferably, R₅ is C₁-C₆alkylamino or C₃-C₈cycloalkylamino;

[0119] (18) m is one;

[0120] (19) n is one;

[0121] (20) p is 0; and combinations of (1) through (20) above.

[0122] A preferred embodiment of the present invention is directed tostructurally novel compounds represented by the following generalformula (II):

[0123] wherein

[0124] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0125] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0126] Preferably R₁ is hydrogen;

[0127] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0128] R₃ is selected from hydrogen or C₁-C₈ alkyl; preferably, R₃ ishydrogen;

[0129] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0130] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0131] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0132] Preferably, R₅ is selected from amino, C₁-C₆alkylamino,C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆dialkylamino;

[0133] m is an integer selected from 0, 1, 2 or 3;

[0134] n is an integer selected from 1 or 2;

[0135] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0136] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0137] Preferred compounds of formula (II) are those wherein

[0138] (1) A₁ is an unsubstituted or substituted amino acid residueselected from the group consisting of phenylalanine, cyclohexylalanine,alanine, β-alanine, heteroarylalanine, naphthylalanine,homophenylalanine, arylglycine, heteroarylglycine, aryl-β-alanine, andheteroaryl-β-alanine wherein the substituents on the amino acid areindependently selected from one or more of halogen, C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino, guanidino,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄alkylsulfonyl,C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄alkenyl, alkynyl, or nitro;

[0139] (2) more preferably, A₁ is an unsubstituted or substituted aminoacid residue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine, wherein the substituents onthe amino acid are independently selected from one or more of halogen,C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0140] (3) even more preferably, A₁ is an unsubstituted amino acidresidue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine;

[0141] (4) most preferably, A₁ is phenylalanine or cyclohexylalanine;

[0142] (5) A₂ is an amino acid selected from the group consisting ofarginine, homoarginine, 2,4-diaminobutyric acid (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), 2,3diaminopropionic acid (optionally substituted with acyl, C₁-C₄alkyl,aroyl, amidino, or MeC(NH)—), glutamine, and lysine (optionallysubstituted with acyl, C₁-C₄alkyl, aroyl, amidino or MeC(NH)—);

[0143] (6) preferably, A₂ is an amino acid selected from the groupconsisting of arginine, homoarginine, 2,4-diaminobutyric acid,2,3-diaminopropionic acid, glutamine, and lysine;

[0144] (7) more preferably, A₂ is arginine;

[0145] (8) R₁ is hydrogen;

[0146] (9) R₂ is selected from hydrogen, C₁-C₈alkyl, aryloxycarbonyl,C₁-C₈alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0147] (10) more preferably, R₂ is selected from C₁-C₈alkylcarbonyl,aryloxycarbonyl, arylaminocarbonyl, and ar(C₁-C₈alkoxy)carbonyl, whereinsaid aryl, ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl areoptionally substituted with one or more of halogen, C₁-C₈alkyl, andC₁-C₈alkoxy;

[0148] (11) most preferably, R₂ is selected from acetyl, Fmoc, andp-methoxyphenylaminocarbonyl;

[0149] (12) R₃ is hydrogen;

[0150] (13) R₄ is substituted aryl, where the substituents on the arylare independently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0151] (14) more preferably, R₄ is substituted aryl, where thesubstituents on the aryl are one to three halogen substituents;

[0152] (15) most preferably, R₄ is 4-fluorophenyl;

[0153] (16) R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0154] (17) preferably, R₅ is C₁-C₆alkylamino or C₃-C₈cycloalkylamino;

[0155] (18) m is one;

[0156] (19) n is one;

[0157] (20) p is 0; and combinations of (1) through (20) above.

[0158] p is an integer selected from 0 or 1; preferably, p is 0; and

[0159] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0160] Another preferred embodiment of the present invention is directedto structurally novel compounds represented by the following generalformula (III):

[0161] wherein

[0162] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0163] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl, anddiheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 1 or A₂ when p is 0;

[0164] Preferably R₁ is hydrogen;

[0165] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0166] R₃ is selected from hydrogen or C₁-C₈ alkyl; preferably, R₃ ishydrogen;

[0167] R₄ is selected from unsubstituted or substituted aryl,arC₁-C₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0168] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0169] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0170] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0171] m is an integer selected from 0, 1, 2 or 3;

[0172] n is an integer selected from 1 or 2;

[0173] p is an integer selected from 0 or 1; preferably, p is 0;

[0174] preferably, the point of attachment of—N(R₃)-A₁-A₂-(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0175] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0176] Preferred compounds of formula (III) are those wherein

[0177] (1) A₁ is an unsubstituted or substituted amino acid residueselected from the group consisting of phenylalanine, cyclohexylalanine,alanine, β-alanine, heteroarylalanine, naphthylalanine,homophenylalanine, arylglycine, heteroarylglycine, aryl-β-alanine, andheteroaryl-β-alanine wherein the substituents on the amino acid areindependently selected from one or more of halogen, C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino, guanidino,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄alkylsulfonyl,C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄alkenyl, alkynyl, or nitro;

[0178] (2) more preferably, A₁ is an unsubstituted or substituted aminoacid residue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine, wherein the substituents onthe amino acid are independently selected from one or more of halogen,C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0179] (3) even more preferably, A₁ is an unsubstituted amino acidresidue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine;

[0180] (4) most preferably, A₁ is phenylalanine or cyclohexylalanine;

[0181] (5) A₂ is an amino acid selected from the group consisting ofarginine, homoarginine, 2,4-diaminobutyric acid (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), 2,3diaminopropionic acid (optionally substituted with acyl, C₁-C₄alkyl,aroyl, amidino, or MeC(NH)—), glutamine, and lysine (optionallysubstituted with acyl, C₁-C₄alkyl, aroyl, amidino or MeC(NH)—);

[0182] (6) preferably, A₂ is an amino acid selected from the groupconsisting of arginine, homoarginine, 2,4-diaminobutyric acid,2,3-diaminopropionic acid, glutamine, and lysine;

[0183] (7) more preferably, A₂ is arginine;

[0184] (8) R₁ is hydrogen;

[0185] (9) R₂ is selected from hydrogen, C₁-C₈alkyl, aryloxycarbonyl,C₁-C₈alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0186] (10) more preferably, R₂ is selected from C₁-C₈alkylcarbonyl,aryloxycarbonyl, arylaminocarbonyl, and ar(C₁-C₈alkoxy)carbonyl, whereinsaid aryl, ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl areoptionally substituted with one or more of halogen, C₁-C₈alkyl, andC₁-C₈alkoxy;

[0187] (11) most preferably, R₂ is selected from acetyl, Fmoc, andp-methoxyphenylaminocarbonyl;

[0188] (12) R₃ is hydrogen;

[0189] (13) R₄ is substituted aryl, where the substituents on the arylare independently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0190] (14) more preferably, R₄ is substituted aryl, where thesubstituents on the aryl are one to three halogen substituents;

[0191] (15) most preferably, R₄ is 4-fluorophenyl;

[0192] (16) R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0193] (17) preferably, R₅ is C₁-C₆alkylamino or C₃-C₈cycloalkylamino;

[0194] (18) m is one;

[0195] (19) n is one;

[0196] (20) p is 0; and combinations of (1) through (20) above.

[0197] Still another preferred embodiment of the present invention isdirected to structurally novel compounds represented by the followinggeneral formula (IV):

[0198] wherein

[0199] A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0200] R₁ and R₂ are each independently selected from hydrogen,C₁-C₈alkyl, ar(C₁-C₈)alkyl, C₁-C₈alkoxycarbonyl, aryloxycarbonyl,ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylcarbonyl,ar(C₁-C₈)alkylcarbonyl, aminocarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,ar(C₁-C₈)alkylaminocarbonyl, diar(C₁-C₈)alkylaminocarbonyl,heterocyclylcarbonyl, heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, heteroaryl(C₁-C₈)alkylaminocarbonyl,diheteroaryl(C₁-C₈)alkylaminocarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxyhydroxy, cyano, amino, and nitro; R₁ and R₂ are covalently bonded to theN-terminus of A₃ when p is 0 or A₂ when p is 1;

[0201] Preferably R₁ is hydrogen;

[0202] Preferably, R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0203] R₃ is selected from hydrogen or C₁-C₈alkyl; preferably, R₃ ishydrogen;

[0204] R₄ is selected from unsubstituted or substituted aryl,arC₁-₈alkyl, C₃C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl,where the substituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroarylor heteroaryl(C₁-C₈)alkyl, group are independently selected from one ormore of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl,C₁-C₈alkoxy, hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0205] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆alkyl, C₃-C₆cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0206] R₅ is selected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino,arylamino, arC₁-C₈alkylamino, C₃-C₈cycloalkylamino,heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈alkyl-N-methylamino,C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino;

[0207] Preferably, R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0208] m is an integer selected from 0, 1, 2 or 3;

[0209] n is an integer selected from 1 or 2;

[0210] p is an integer selected from 0 or 1; preferably, p is 0;

[0211] preferably, the point of attachment of—N(R₃)—A₁—A₂—(A₃)_(p)—R₁(R₂) is the 5 or 6 position of the coreheterocyclic ring; more preferably, the point of attachment is the 6position; and

[0212] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0213] Preferred compounds of formula (IV) are those wherein

[0214] (1) A₁ is an unsubstituted or substituted amino acid residueselected from the group consisting of phenylalanine, cyclohexylalanine,alanine, β-alanine, heteroarylalanine, naphthylalanine,homophenylalanine, arylglycine, heteroarylglycine, aryl-β-alanine, andheteroaryl-β-alanine wherein the substituents on the amino acid areindependently selected from one or more of halogen, C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino, guanidino,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄alkylsulfonyl,C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄alkenyl, alkynyl, or nitro;

[0215] (2) more preferably, A₁ is an unsubstituted or substituted aminoacid residue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine, wherein the substituents onthe amino acid are independently selected from one or more of halogen,C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0216] (3) even more preferably, A₁ is an unsubstituted amino acidresidue selected from the group consisting of phenylalanine,cyclohexylalanine, and heteroarylalanine;

[0217] (4) most preferably, A₁ is phenylalanine or cyclohexylalanine;

[0218] (5) A₂ is an amino acid selected from the group consisting ofarginine, homoarginine, 2,4-diaminobutyric acid (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), 2,3diaminopropionic acid (optionally substituted with acyl, C₁-C₄alkyl,aroyl, amidino, or MeC(NH)—), glutamine, and lysine (optionallysubstituted with acyl, C₁-C₄alkyl, aroyl, amidino or MeC(NH)—);

[0219] (6) preferably, A₂ is an amino acid selected from the groupconsisting of arginine, homoarginine, 2,4-diaminobutyric acid,2,3-diaminopropionic acid, glutamine, and lysine;

[0220] (7) more preferably, A₂ is arginine;

[0221] (8) R₁ is hydrogen;

[0222] (9) R₂ is selected from hydrogen, C₁-C₈alkyl, aryloxycarbonyl,C₁-C₈alkoxycarbonyl, C₁-C₈alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy;

[0223] (10) more preferably, R₂ is selected from C₁-C₈alkylcarbonyl,aryloxycarbonyl, arylaminocarbonyl, and ar(C₁-C₈alkoxy)carbonyl, whereinsaid aryl, ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl areoptionally substituted with one or more of halogen, C₁-C₈alkyl, andC₁-C₈alkoxy;

[0224] (11) most preferably, R₂ is selected from acetyl, Fmoc, andp-methoxyphenylaminocarbonyl;

[0225] (12) R₃ is hydrogen;

[0226] (13) R₄ is substituted aryl, where the substituents on the arylare independently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl;

[0227] (14) more preferably, R₄ is substituted aryl, where thesubstituents on the aryl are one to three halogen substituents;

[0228] (15) most preferably, R₄ is 4-fluorophenyl;

[0229] (16) R₅ is selected from amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₈cycloalkylamino, arylamino, arC₁-C₆alkylamino,heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂,heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl,C₁-C₆alkylamino or C₁-C₆ dialkylamino;

[0230] (17) preferably, R₅ is C₁-C₆alkylamino or C₃-C₈cycloalkylamino;

[0231] (18) m is one;

[0232] (19) n is one;

[0233] (20) p is 0; and combinations of (1) through (20) above.

[0234] The compounds of the present invention are thrombin receptorantagonists and as such are useful in treating thrombosis, restenosis,hypertension, heart failure, arrhythmia, myocardial infarction,glomerulonephritis, reocclusion following thrombolytic therapy,reocclusion following angioplasty, inflammation, angina, stroke,atherosclerosis, ischemic conditions, a vaso-occlusive disorder,neurodegenerative disorders, angiogenesis and related disorders andcancer. These compounds are also useful as antithrombotics inconjunction with fibrinolytic therapy (e.g., t-PA or streptokinase).

[0235] In the compounds of formulae (I), (II), (III) and (IV), the aminoacid residues comprising the A₁, A₂ and A₃ substituents are attached tothe adjacent moiety so that the amino-terminus (N-terminus) of the aminoacid is drawn on the right and the carboxy-terminus of the amino acid isdrawn on the left. So, for example, in Compound 1, where A₁ isphenylalanine and A₂ is arginine, the carbonyl group of thephenylalanine residue is attached to the N(R₃) group on the core ringand the amino terminus is attached to the carbonyl group of the secondamino acid residue.

[0236] When a particular group is “substituted” (e.g., Phe, aryl,heteroalkyl, heteroaryl), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

[0237] Amino acid abbreviations are defined below: Ala Alanine β-Alabeta-Alanine Arg Arginine hArg Homoarginine Cha Cyclohexylalanine CitCitrulline Cys Cysteine Dbu 2,4-Diaminobutyric acid Dpr Diaminopropionicacid Gln Glutamine Gly Glycine His Histidine Lys Lysine Met MethionineNal Naphthylalanine Orn Ornithine Phe Phenylalanine hPheHomophenylalanine Pro Proline Pyr-Ala Pyridylalanine Ser Serine hSerHomoserine Tic Tetrahydroisoquinoline-3-COOH Tyr Tyrosine Val Valine

[0238] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl” substituentrefers to a group of the formula

[0239] The compounds of the present invention may also be present in theform of a pharmaceutically acceptable salt. The pharmaceuticallyacceptable salt generally takes a form in which the basic nitrogen isprotonated with an inorganic or organic acid. Representative organic orinorganic acids include hydrochloric, hydrobromic, hydriodic,perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic,lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic,mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic,oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.

[0240] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0241] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0242] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0243] As used herein, unless otherwise noted “alkyl” and “alkoxy”whether used alone or as part of a substituent group, include straightand branched chains having 1 to 8 carbon atoms, or any number withinthis range. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyland 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from thepreviously described straight or branched chain alkyl groups. Cycloalkylgroups contain 3 to 8 ring carbons and preferably 5 to 7 carbons.Similarly, alkenyl and alkynyl groups include straight and branchedchain alkenes and alkynes having 1 to 8 carbon atoms, or any numberwithin this range.

[0244] The term “aryl” as used herein refers to an unsubstituted orsubstituted aromatic group such as phenyl and naphthyl. The term “aroyl”refers to the group —C(O)-aryl.

[0245] The term “heteroalkyl” as used herein represents an unsubstitutedor substituted stable three to seven membered monocyclic saturated ringsystem which consists of carbon atoms and from one to three heteroatomsselected from N, O or S, and wherein the nitrogen or sulfur heteroatomsmay optionally be oxidized, and the nitrogen heteroatom may optionallybe quaternized. The heteroalkyl group may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of such heteroalkyl groups include, but are not limited toazetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, oxopiperazinyl,oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl,tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone and oxadiazolyl. Preferredheteroalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, azetidinyl and tetrahydrothiazolyl.

[0246] The term “heteroaryl” as used herein represents an unsubstitutedor substituted stable five or six membered monocyclic aromatic ringsystem or an unsubstituted or substituted nine or ten memberedbenzo-fused heteroaromatic ring system or bicyclic heteroaromatic ringsystem which consists of carbon atoms and from one to four heteroatomsselected from N, O or S, and wherein the nitrogen or sulfur heteroatomsmay optionally be oxidized, and the nitrogen heteroatom may optionallybe quaternized. The heteroaryl group may be attached at any heteroatomor carbon atom that results in the creation of a stable structure.Examples of heteroaryl groups include, but are not limited to pyridyl,pyridazinyl, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl,pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl adeninyl or quinolinyl. Prefered heteroaryl groupsinclude pyridyl, pyrrolyl, pyrazinyl, thiadiazolyl, pyrazolyl, thienyl,triazolyl and quinolinyl.

[0247] The term “aralkyl” means an alkyl group substituted with one, twoor three aryl groups (e.g., benzyl, phenylethyl, diphenylmethyl,triphenylmethyl). Similarly, the term “aralkoxy” indicates an alkoxygroup substituted with an aryl group (e.g., benzyloxy). The termaminoalkyl refers to an alkyl group substituted with an amino group(i.e., -alkyl-NH₂). The term “alkylamino” refers to an amino groupsubstituted with an alkyl group (i.e., —NH-alkyl). The term“dialkylamino” refers to an amino group which is disubstituted withalkyl groups wherein the alkyl groups can be the same or different(i.e., —N-[alkyl]₂).

[0248] The term “acyl” as used herein means an organic radical having 1to 6 carbon atoms (branched or straight chain) derived from an organicacid by removal of the hydroxyl group.

[0249] The term “oxo” refers to the group ═O.

[0250] The term “carbonyl” refers to the group C(O).

[0251] The term “halogen” shall include iodine, bromine, chlorine andfluorine.

[0252] Whenever the term “alkyl” or “aryl” or either of their prefixroots appear in a name of a substituent (e.g., aralkyl, dialkylamino) itshall be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)shall refer independently to the number of carbon atoms in an alkyl orcycloalkyl moiety or to the alkyl portion of a larger substituent inwhich alkyl appears as its prefix root.

[0253] As used herein, the term “phosgene equivalent” represents theclass of carbonic acid derivatives which include 4-nitrophenylchloroformate, phosgene or “COCl₂,” phenyl chloroformate, triphosgene or“(CCl₃O)₂CO,” carbonyldiimidazole, diethyl carbonate or diphenylcarbonate.

[0254] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[0255] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.Accordingly, pharmaceutical compositions containing the compounds of thepresent invention as the active ingredient as well as methods ofpreparing the instant compounds are also part of the present invention.

[0256] Particularly preferred compounds of the present invention shownin Table 1 (compounds of formula (V)) and Table 2 (compounds of formula(VI)), as follows; the amino acids bear the “L” absolute configurationunless denoted otherwise. TABLE 1 Indolyl Peptidomimetics As ThrombinReceptor (PAR-1) Antagonists

Cmpd No. A₁ A₂ R₂ R₅ R₄ 1 Phe Arg Fmoc —NH(propyl) 4-Fluorophenyl 2 PheArg Acetyl —NH(propyl) 4-Fluorophenyl 3 Phe Arg PhNHCO— —NH(propyl)4-Fluorophenyl 4 Phe Arg Cbz —NH(propyl) 4-Fluorophenyl 5 Phe Arg(4-OMe)PhNHCO— —NH(propyl) 4-Fluorophenyl 6 Phe Arg

—NH(propyl) 4-Fluorophenyl 7 Phe Arg Acetyl —NH(cyclopentyl)4-Fluorophenyl 8 Phe Arg (4-OMe)PhNHCO— —NH(cyclopentyl) 4-Fluorophenyl9 Phe Arg Fmoc —NH(cyclopentyl) 4-Fluorophenyl 10 Phe Arg (4-Cl)PhNHCO——NH(propyl) 4-Fluorophenyl 11 Phe Arg (4-F)PhNHCO— —NH(propyl)4-Fluorophenyl 12 Phe Arg (4-OMe)PhNHCO— —NH(cyclopentyl) 4-Fluorophenyl

[0257] TABLE 2 Indolyl Peptidomimetics As Thrombin Receptor (PAR-1)Antagonists

Cmpd No. A₁ A₂ R₂ R₅ R₄ 13 Phe Arg Acetyl —NH(cyclopentyl)4-Fluorophenyl 14 Phe Phe Acetyl —NH(cyclopentyl) 4-Fluorophenyl 15 PheArg H —NH(cyclopentyl) 4-Fluorophenyl 16 Phe Arg Fmoc —NH(cyclopentyl)4-Fluorophenyl 17 Phe Arg Benzyl-CO— —NH(cyclopentyl) 4-Fluorophenyl 18Phe Arg (4-OMe)PhCH₂CO— —NH(cyclopentyl) 4-Fluorophenyl 19 Phe Arg Cbz—NH(cyclopentyl) 4-Fluorophenyl 20 Phe Arg Acetyl —NH₂ 4-Fluorophenyl 21Cha Arg Acetyl —NH(cyclopentyl) 4-Fluorophenyl

[0258] The antagonists of the present invention may be prepared viaeither solution-phase or solid-phase methods. All compounds presented inTable 1 and able 2 may be prepared using the methodology outlined ingeneric schemes AA through DD.

[0259] Nitroindole AA1 was alkylated with an appropriately substitutedalkyl or arylalkyl halide in the presence of a base such as cesiumcarbonate, potassium carbonate and the like also in the presence of asolvent such as DMF to provide a 1-substututed indole intermediate. Theresulting intermediate was reacted with an amine such as pyrrolidine,piperidine and the like while dissolved in an organic acid such asglacial acetic acid in the presence of formaldehyde also in glacialacetic acid to provide a 3-substututed indole intermediate. The nitrogroup of the resulting intermediate was then reduced to an amino groupby reaction with 1,1-dimethylhydrazine in the presence of an alcoholsolvent such as MeOH and charcoal and ferric chloride hexahydrate whichprovided intermediate AA2.

[0260] Intermediate AA2 was coupled to an appropriately protected aminoacid A₁ using standard peptide coupling conditions well known to thoseskilled in the art. An example of such conditions include reacting theamino indole with the amino acid A₁ in the presence of a solvent such asDCM, also in the presence of a peptide coupling reagent such as EDC, DCCand the like, also in the presence of standard coupling reactionadditives such as HOBT, and also in the presence of a non-nucleophilicamine such as TEA, DIPEA and the like. The protecting group on the aminoacid is then removed using conditions well known to those skilled in theart. An example of such conditions include treatment of a Boc-protectedamino acid derivative with a solution of a strong acid such as TFA, HCland the like in an appropriate solvent such as CH₂Cl₂ or treatment of anFmoc protected amino acid derivative with an organic base such aspiperidine in an appropriate solvent such as dioxane. This reactionsequence gives rise to intermediate AA3.

[0261] The substituent R₃ may be introduced at this stage by reactingintermediate AA3 with an alkyl halide R₃-X such as methyl iodide, ethylbromide and the like in the presence of a strong base such as NaH andthe like, also in the presence of an appropriate solvent such as DMF andthe like. Other standard alkylation conditions well known to thoseskilled in the art may also be used to introduce substituent R₃.Alternatively, R₃ may remain hydrogen.

[0262] The peptide coupling/deprotection sequence described above may beperformed in an iterative manner which provides intermediates AA4 andAA6. These intermediates may be subsequently functionalized with R₁ andR₂ substituents upon reaction of the terminal amino group with anelectrophilic agent such as an alkyl halide, an acyl halide, anaryl(C₁-C₆)alkyl halide and the like to provide target compounds AA5 andAA7.

[0263] Nitroindole AA1 was alkylated with an appropriately substitutedalkyl or aryl(C₁-C₆)alkyl halide in the presence of a base such ascesium carbonate, potassium carbonate and the like also in the presenceof a solvent such as DMF to provide a 1-substituted indole intermediate.The nitro group of the resulting intermediate was then reduced to anamino group by reaction with SnCl₂ in the presence of an alcohol solventsuch as MEOH to provide intermediate BB1. The resulting amino group wasprotected using conditions known to those skilled in the art whichprovided intermediate BB2.

[0264] Intermediate BB2 then can undergo a Mannich-type reaction with analkyl amine in the presence of formalin and an acid like ACOH to giveintermediate BB3. The 3-substituted indole BB3 is then attached to atrityl resin and the amino substituent on the indole ring is deprotectedwhich gives rise to intermediates BB4. Both reactions are performedusing methodology well known to those skilled in the art as illustratedin the scheme.

[0265] Intermediate BB4 is then subjected to an iterative sequence ofamino acid coupling/deprotection as described before relative to SchemeAA to give intermediates BB5, BB6, and BB10. In any of these three aminoacid coupled intermediates, the R₃ substituent may be introduced beforedeprotection of the terminal amino group by alkylation reactions knownto those skilled in the art and discussed previously as related toScheme AA. Alternatively, R₃ may remain hydrogen.

[0266] Intermediates BB10and BB6 may be further functionalized with R₁and/or R₂ substituents in the same manner as described in Scheme AA forintermediates AA4 and AA6. Following the addition of the R₁ and/or R₂substituents, the molecules are cleaved from the trityl resin bytreatment with anisole in TFA, a procedure well known to those skilledin the art. This cleavage gives rise to targets BB8 and BB12.

[0267] The 3-indole substituent in targets BB6 and BB12 may be furtherfunctionalized at the —NH site by reaction with an appropriate alkylhalide, alkenyl halide, or cycloalkyl halide and the like underconditions known to those skilled in the art to provide additionaltargets BB9 and BB13.

[0268] An appropriately nitro substituted indole CC1 (Scheme CC) wastreated with aqueous NaNO₂ under acidic conditions (pH from about pH 1to about pH 2) to give (via nitrosation, G. Buchi, J. Am. Chem. Soc.1986, 108, 4115) 3-indazolecarboxaldehyde CC2. Reductive amination ofCC2 with an amine such as pyrrolidine and a reducing agent such assodium triacetoxyborohydride introduced the R₅ group and afforded CC3.Alkylation of CC3 with a substituted aralkyl or heteroarylalkyl halideand a base such as potassium hydroxide in an aprotic solvent such as THFto give an intermediate, which was reduced in a classical manner with,for example, iron and acetic acid or with a newer method such asdimethyl hydrazine and iron to give aminoindazole intermediate CC4.

[0269] An appropriately nitro substituted benzimidazolone DD1 (SchemeDD) was alkylated with a substituted aralkyl or heteroaryl alkyl halideand a base such as sodium hydride in a dipolar aprotic solvent such asDMF to give DD2 as a mixture of two regioisomers. Two isomers wereseparated by silica gel column and then alkylated, with an aminoalkylhalide and a base such as sodium hydride in a dipolar aprotic solventsuch as DMF to give two regioisomers DD3, respectively. Reduction ofnitro group in DD3 in a classical manner with for example iron andacetic acid or with a newer method such as dimethyl hydrazine and ironto give aminobenzimidazolone intermediate DD4.

[0270] The aminoindazoles CC4 and the aminobenzimidazolones DD4 may besubjected to the same peptide coupling/deprotection sequences and thereactions used to introduce R₁, R₂ and R₃ as described in previousschemes which will provide additional compounds of Formula (I).

[0271] The utility of the compounds to treat PAR-1 mediated disorders(e.g., thrombotic disorders) can be determined according to theprocedures described herein. The present invention therefore provides amethod of treating PAR-1 mediated disorders (e.g., thrombotic disorders)in a subject in need thereof which comprises administering any of thecompounds as defined herein in a quantity effective to treat PAR-1mediated disorders. The compound may be administered to a patient by anyconventional route of administration, including, but not limited to,intravenous, oral, subcutaneous, intramuscular, intradermal andparenteral.

[0272] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier.

[0273] To prepare the pharmaceutical compositions of this invention, oneor more compounds of formula (I) or salt thereof of the invention as theactive ingredient, is intimately admixed with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, though other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, from about 0.03 mg/kg to about100 mg/kg (preferred from about 0.1 mg/kg to about 30 mg/kg) of acompound of the present invention and may be given at a dosage fromabout 0.1 mg/kg/day to about 300 mg/kg/day (preferred from about 1mg/kg/day to about 50 mg/kg/day). The dosages, however, may be varieddepending upon the requirement of the patients, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

[0274] Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present inventionor a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pills of thenovel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

[0275] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0276] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0277] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

[0278] The method of treating PAR-1 mediated disorders (e.g., thromboticdisorders) described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg to about100 mg, preferably from about 5 to about 50 mg, of the compound, and maybe constituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixers,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

[0279] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0280] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0281] The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

[0282] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0283] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0284] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of PAR-1 mediated disorders is required.

[0285] The daily dosage of the products may be varied over a wide rangefrom about 0.01 mg to about 1,000 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 mg of the active ingredientfor the symptomatic adjustment of the dosage to the patient to betreated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.01 mg/kg to about 100 mg/kg of body weightper day. Preferably, the range is from about 0.03 mg/kg to about 10mg/kg of body weight per day. The compounds may be administered on aregimen of about 1 time to about 4 times per day.

[0286] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[0287] Biology

[0288] The compounds of the present invention are thrombin receptor(PAR-1) antagonists. The compounds interrupt platelet activation inducedby thrombin's proteolytic cleavage of its platelet surface receptor, andthereby inhibit platelet aggregation. Such compounds are, therefore,useful in treating platelet-mediated thrombotic disorders (e.g.,arterial and venous thrombosis, acute myocardial infarction, reocclusionfollowing thrombolytic therapy and angioplasty, and a variety ofvaso-occlusive disorders) and other PAR-1 mediated disorders.

[0289] In Vitro Thrombin Receptor Binding Assay

[0290] CHRF membranes (Jones, Biochim. Biophys. Acta 1992, 1136, 272)are thawed from −70° C., centrifuged at maximum speed for 5 min, washedtwice with binding buffer (50 mM HEPES containing 5 mM MgCl₂ and 0.1%BSA), and re-suspended in binding buffer (25 μg/100 mL). 100 μL ofmembranes are added to the 24-Wallac plates and delivered to the Tomtechapparatus. In a typical experiment, 6 μL of samples (from a 125 μg/mLintermediary plate, 20% DMSO) and 44 μL buffer are delivered to theplates (final conc. of compounds is 3.7 μg/mL, 0.6% DMSO). Similarly, 6μL 20% DMSO and 44 μL buffer are delivered to both column 1 (NSB) andcolumn 12 (TB). 10 μL Ser-pFPhe-Har-Leu-Har-Lys-Tyr-NH₂ (721-40; 500 μMin deionized water) is added to column 1.50 μL tritiated 721-40(specific activity 46 Ci/mmol) is added to all the wells. The plates aremixed well for 20 seconds, incubated for 30 min, and then harvested with10 mM HEPES/138 mM NaCl using the Skatron harvester. The filters (GF/CBrandel FPXLR 296) are presoaked 3 h in 0.5% polyethylenimine inHEPES/0.1M N-acetylglucosamine) are set in saran wrap and dried for 3min in the microwave, and placed in sample bags (Wallac 1450-432). 4.5mL scintillation fluid (Wallac, Betaplate Scint 1205-440) is added. Thebags are sealed, placed in filter cassettes (Wallac 1450-104), andanalyzed on the microbeta counter.

[0291] In Vitro Inhibition Of Thrombin- and SFLLRN-NH₂-InducedGel-Filtered Platelet Aggregation Assay

[0292] Platelet Rich Plasma concentrate (Biological Specialties, Inc) isgel filtered (Sepharose 2B, Pharmacia) in Tyrode's buffer (140 mM NaCl,2.7 mM KCl, 12 mM NaHCO₃, 0.76 mM Na₂HPO₄, 5.5 mM dextrose, 5.0 mMHepes, and 2 mg/ml BSA @ pH 7.4). The gel-filtered platelets are dilutedwith Tyrode's buffer (143,000 platelets/μl, final platelet count perwell), compound solution in buffer, and 2 mM CaCl₂ in a 96 well plate.Platelet aggregation is initiated by the addition of human α-thrombin(American Diagnostica, 0.113 nM-0.187 nM) or SFLLRN-NH₂ (2 μM) shown toachieve 80% aggregation (0.015-0.025 NIH U/ml, 0.113 nM-0.187 nM). Theassay plate is stirred constantly. Platelet aggregation is monitored byintermittently placing the plate in a microplate reader (MolecularDevices) to read optical density (650 nM, ΔSOFT) at 0 and 5 minutesafter the thrombin addition. Aggregation was calculated to be thedecrease in optical density between the time 0 and 5 minutemeasurements. All samples were tested in duplicate wells on the sameplate.

[0293] Table 3 shows the biological activity of the compounds of thepresent invention. Table 3 contains IC₅₀ values (μM) of the compoundsagainst platelet aggregation stimulated by thrombin and IC₅₀ values (μM)in a thrombin receptor (PAR-1) binding assay. TABLE 3 BiologicalActivity Platelet Platelet Thrombin Aggregation Aggregation ReceptorCmpd Thrombin SFLLRN-NH2 Binding No. IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 151.6 43.7 2 80 3.2 3 >100 4 42 5 >100 6 >100 7 8 75.4 9 88.6 10 >10011 >100 12 37.3 5.3 20 13 50.1 4 5.2 14 92 2.6 4.8 15 >100 16 15.6 1.87.6 17 44.5 9.8 10.4 18 61.7 16.4 11.7 19 18.7 11.1 2.4 20 >100 21 4.73.2 10.7

EXAMPLES

[0294] General Procedures: Resins and protected amino acids werepurchased from Novabiochem, Bachem Bioscience, Advanced ChemTech orSynthe Tech. All other chemicals were obtained from commercial suppliersand used without further purification. ¹H and ¹³C NMR spectra wererecorded on a Bruker AC 300B (300 MHz proton) or a Bruker AM-400 (400MHz proton) spectrometer with Me₄Si as an internal standard (s=singlet,d=doublet, t=triplet, br=broad). APCI-MS and ES-MS were recorded on a VGPlatform II mass spectrometer, methane was used for chemical ionization,unless noted otherwise. Accurate mass measurements were obtained byusing a VG ZAB 2-SE spectrometer in the FAB mode. TLC was performed withWhatman 250-μm silica gel plates. Preparative TLC was performed withAnaltech 1000-μm silica gel GF plates. Flash column chromatography wasconducted with flash column silica gel (40-63 μm) and columnchromatography was conducted with standard silica gel. HPLC separationswere carried out on three Waters PrepPak® Cartridges (25×100 mm,Bondapak® C18, 15-20 μm, 125 Å) connected in series; detection was at254 nm on a Waters 486 UV detector. Analytical HPLC was carried out on aSupelcosil ABZ+PLUS column (5 cm×2.1 mm), with detection at 254 nm on aHewlett Packard 1100 UV detector. Microanalysis was performed byRobertson Microlit Laboratories, Inc.

[0295] In the examples and throughout this application, the followingabbreviations have the meanings recited hereinafter: Ac Acetyl ACNAcetonitrile Bn Benzyl Boc t-Butoxycarbonyl Cbz Carbobenzyloxy DCC1,3-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM DichloromethaneEDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide DICDiisopropylcarbodiimide DIEA Diisopropylethylamine DMF N,N-Dimethylformamide Et Ethyl EtOAc Ethyl acetate Fmoc9-Fluorenylmethoxycarbonyl h Hour HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateHOAc Acetic acid HOBT Hydroxybenzotriazole Me Methyl min Minute Pmc2,2,5,7,8-Pentamethylchroman-6-sulfonyl rt Room temperature TEATriethylamine THF Tetrahydrofuran TFA Trifluoroacetic acid TLC Thinlayer chromatography

Example 1 Synthesis of Compound 17 (Scheme AA)5-Guanidino-2-phenylacetylamino-pentanoic acid{1-[1-(4-fluoro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-5-ylcarbamoyl]-2-phenyl-ethyl}-amide

[0296]

[0297] 6-Nitroindole A1 (6.57 g, 40.5 mmol) was dissolved in dry DMFunder argon, cesium carbonate (13.2 g, 40.5 mmol) was added and themixture was stirred at about 50° C. for about 30 min. After cooling toabout rt, the mixture was stirred while 4-fluorobenzyl bromide (7.70 g,40.7 mmol) in DMF was added dropwise; then the reaction was stirred atrt overnight. The solution was then partitioned between DCM and water.The organic layers were combined, washed with water, dried (MgSO₄) andevaporated in vacuo. The resulting residue dissolved in glacial aceticacid was added dropwise to a stirring solution of pyrrolidine (13.9 g,195.4 mmol) and formaldehyde (37%, 15.9 g, 195.9 mmol) in glacial aceticacid and the reaction was stirred at rt overnight. The reaction pH wasbrought to neutral by careful addition of 50% w/w NaOH. The mixture wasextracted with DCM, washed with saturated NaHCO₃, dried (MgSO4) andevaporated in vacuo. The resulting solid was combined in MeOH withcharcoal and ferric chloride hexahydrate (0.30 g, 1.1 mmol),1,1-dimethylhydrazine (10.6 g, 176.6 mmol) was then added and thereaction was refluxed for about 16 h. After cooling to about rt, thereaction was filtered through dicalite and the filtrate was evaporatedin vacuo to afford A2. ES-MS m/z 324 (MH⁺).

[0298] To a solution of A2 (4.70 g, 14.5 mmol) in DCM, ED.CHCl (2.78 g,14.5 mmol), HOBT (5 mg), TEA (1.5 g, 14.5 mmol), and BOC-Phe-OH (3.90 g,14.5 mmol) were added; then the reaction stirred at rt overnight. Thereaction was extracted with saturated NH₄Cl and the organic layers werecombined and evaporated in vacuo. This was purified by flash columnchromatography using DCM/EtOH (95:5 to 90:10) to afford 3.45 g of asolid. The resulting solid (3.30 g, 5.78 mmol) was treated withTFA/CH₂Cl₂ (50/50) overnight at rt. The reaction was evaporated in vacuoand partitioned between DCM and saturated NaHCO₃. The organic layerswere combined, filtered and evaporated in vacuo to give A3 (2.3 g).ES-MS m/z 471 (MH⁺).

[0299] To a solution of A3 in DCM was added HOBT (5 mg), TEA (0.51 g,5.0 mmol), and Fmoc-Arg(PMC)-OH (3.24 g, 4.89 mmol). ED.CHCl (0.94 g,4.90 mmol) was added and the reaction stirred overnight at rt. Thereaction was extracted with saturated NH₄Cl and the organic layers werecombined and evaporated in vacuo. This was purified by flash columnchromatography using DCM/MeOH (100:0 to 95:5) to afford 3.10 g of solidA4. ES-MS m/z 1116 (MH⁺).

[0300] A4 was dissolved in 1,4-dioxane (16 mL) and piperidine (4 mL) wasadded and the reaction stirred for 3 h at rt. The reaction wasevaporated in vacuo and triturated with ether/hexane to afford A5. ES-MSm/z 894 (MH⁺).

[0301] To a solution of A5 (0.80 g, 0.90 mmol) and TEA (0.12 g, 1.2mmol) in DCM was added a dropwise solution of phenylacetyl chloride(0.14 g, 0.90 mmol) in DCM and the reaction was stirred at rt overnight.The reaction was evaporated in vacuo and partitioned between DCM andsaturated NH₄Cl. The organic layers were combined, evaporated in vacuo,and triturated with ether/hexane to give a solid which was treated witha solution (21 mL) of DCM:TFA:anisole (50:50:1) at rt overnight. Thereaction was evaporated in vacuo and purified by reverse-phase HPLC toafford Compound 17. ES-MS m/z 745 (MH⁺).

Example 2 Synthesis of Compound 19 (Scheme B)(1-{1-[1-(4-Fluoro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-5-ylcarbamoyl]-2-phenyl-ethylcarbamoyl}-4-guanidino-butyl)-carbamicacid benzyl ester

[0302]

[0303] To a solution of A5 (0.50 g, 0.56 mmol) and TEA (0.07 g, 0.70mmol) in DCM was added dropwise a solution of benzyl chloroformate (0.10g, 0.56 mmol) in DCM and the reaction stirred at rt overnight. Thereaction was evaporated in vacuo and partitioned between DCM andsaturated NH₄Cl. The organic layers were combined, evaporated in vacuo,and triturated with ether/hexane to give a crude product which waspurified by flash column chromatography using DCM/10-20% EtOH/1-2%NH₄OH) to afford 0.12 g of solid which was treated with a solution ofDCM:TFA (50:50) at rt overnight. The reaction was evaporated in vacuoand purified by reverse-phase HPLC to afford Compound 19. ES-MS m/z 761(MH⁺). Anal. calcd. for C₄₃H₄₉N₈O₄F.2.7 C₂HF₃O₂ (760.92/1068.78): C,54.39; H, 4.88; N, 10.48; F, 16.18. Found: C, 54.87; H, 5.37; N, 9.87;F, 15.99.

Example 3 Synthesis of Compound 16 (Scheme BB)(1-{1[1-(4-Fluoro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-5-ylcarbamoyl]-2-phenyl-ethylcarbamoyl}-4-guanidino-butyl)-carbamicacid 9H-fluoren-9-ylmethyl ester

[0304]

[0305] To a mixture of A4 (1.80 g, 1.6 mmol) and anisole (1.70 g, 15.7mmol) was added TFA and the reaction was stirred at rt overnight. Thereaction was evaporated in vacuo and partitioned between DCM andsaturated NaHCO₃. The organic layers were combined, filtered andevaporated in vacuo. The crude product was purified by reverse-phaseHPLC to give Compound 16. ES-MS m/z 849 (MH⁺). Anal. calcd. forC₅₀H₅₃N₈O₄F.2.5 C₂HF₃O₂.1.0H₂O (849.03/1152.10): C, 57.34; H, 5.03; N,9.73; F, 14.02; KF, 1.56. Found: C, 56.98; H, 5.06; N, 9.69; F, 13.91;KF, 1.52.

Example 4 Synthesis of Compound 21 (Scheme D)2-Acetylamino-5-guanidino-pentanoic acid{2-cyclohexyl-1-[1-(4-fluoro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-5-ylcarbamoyl]-ethyl}-amide

[0306]

[0307] 6-Nitroindole A1 (6.90 g, 42.5 mmol) was dissolved in dry DMFunder argon, cesium carbonate (13.90 g, 42.6 mmol) was added and themixture was stirred at about 50° C. for about 30 min. After cooling toabout rt, the mixture was stirred while 4-fluorobenzyl bromide (8.10 g,42.8 mmol) in DMF was added dropwise; then the reaction was stirred atrt overnight. The solution was then partitioned between DCM and water.The organic layers were combined, washed with water, dried (MgSO₄) andevaporated in vacuo. The resulting residue (10.0 g, 37.0 mmol) and tin(II) chloride (14.0 g, 73.8 mmol) were refluxed in ethanol overnight.The reaction was evaporated in vacuo. Saturated NaHCO₃ was added slowlyto the remaining residue and the solution was stirred for 1 h. Thesolution was filtered and the collected solid was triturated with DCM.The DCM solution was evaporated in vacuo. The remaining residue waspurified by flash column chromatography using CH₂Cl to give 5.50 g ofsolid D1. ES-MS m/z 241 (MH⁺).

[0308] To a solution of D1 (1.38 g, 5.7 mmol) in DCM, ED.CHCl (1.09 g,5.7 mmol), HOBT (5 mg), TEA (0.58 g, 5.7 mmol), and N-BOC-Cha-OH (1.56g, 5.7 mmol) were added. The reaction stirred overnight at rt. Thereaction was extracted with saturated NH₄Cl and the organic layers werecombined and evaporated in vacuo. This was purified by flash columnchromatography using DCM/MeOH (95:5) to afford 2.17 g of solid D2. ES-MSm/z494 (MH⁺).

[0309] A solution of D2 in glacial acetic acid was added dropwise to astirring solution of pyrrolidine (1.40 g, 19.7 mmol) and formaldehyde(37%, 0.66 g, 8.1 mmol) in glacial acetic acid and the reaction wasstirred at rt overnight. The reaction pH was brought to neutral bycareful addition of 50% w/w NaOH. The mixture was extracted with DCM,washed with saturated NaHCO₃, dried (MgSO4) and evaporated in vacuo. Theresulting residue was purified by column chromatography usingacetone:EtOH:NH₄OH (80:20:0.1) to give 1.2 g of solid D3 which wastreated with TFA/CH₂Cl₂ (50/50) overnight at rt. The reaction wasevaporated in vacuo and partitioned between DCM and saturated NaHCO₃.The organic layers were combined, filtered and evaporated in vacuo.ES-MS m/z 477 (MH⁺).

[0310] To the remaining residue D4 in DCM was added HOBT (5 mg), TEA(0.20 g, 2.0 mmol), and Ac-Arg(PMC)—OH (0.95 g, 1.8 mmol). EDC.HCl (0.35g, 1.8 mmol) was added and the reaction stirred overnight at rt. Thereaction was extracted with saturated NH₄Cl and the organic layers werecombined and evaporated in vacuo. The residue was purified by flashcolumn chromatography using gradient DCM:MeOH:NH₄OH to give 0.43 g ofsolid D5 which was treated with a solution of anisole (0.25 g, 2.31mmol) in DCM/TFA (4:1, 50 mL) at rt overnight. The reaction mixture wasevaporated in vacuo and partitioned between DCM and water. The organiclayers were combined and evaporated in vacuo to give the crude product.The crude product was purified by reverse-phase HPLC to give Compound21. ES-MS m/z 675 (MH⁺).

Example 5 Synthesis of Compound 2 (Scheme E)2-Acetylamino-5-guanidino-pentanoic acid{1-[1-(4-fluoro-benzyl)-3-propylaminomethyl-1H-indol-5-ylcarbamoyl]-2-phenyl-ethyl}-amide

[0311]

[0312] To a stirring solution of E1 (1.72 g, 7.1 mmol, prepared usingthe procedure for D1, see Scheme CC) and DIEA (1.25 mL, 7.2 mmol) in DCM(340 mL) was added dropwise a solution of allyl chloroformate (0.75 mL,7.1 mmol) in DCM (100 mL). The reaction was stirred overnight at rt. Thereaction was washed with NH₄Cl (2×) and water (2×). The organic layerwas dried (MgSO₄) and evaporated in vacuo. The resulting residue E2 wasdissolved in glacial acetic acid and the solution was added dropwise toa stirring solution of propylamine (2.83 mL, 34.5 mmol) and formaldehyde(37%, 0.38 g, 13.8 mmol) in glacial acetic acid (46 mL), and thereaction was stirred at rt overnight. The reaction pH was brought toneutral by careful addition of 50% w/w NaOH. The mixture was extractedwith DCM, washed with saturated NaHCO₃, dried (MgSO4) and evaporated invacuo to give a crude product which was purified by flash columnchromatograph using DCM:MeOH:NH₄OH (97:3:1) to afford 1.16 g of E3.

[0313] 2-Chlorotrityl chloride resin (0.27 g, 0.35 mmol; Novabiochem)was agitated (nitrogen bubbling) in a solid phase hour-glass reactor inDMF (20 mL) as E3 (0.28 g, 0.70 mmol) and DIEA (0.30 mL, 1.70 mmol.)were added. The reaction was agitated at rt for about 21 h. The resinwas washed with DMF (1×), DMF/H₂O (1:4, 1×), DMF (3×), THF (3×), DCM(3×), and ether (1×). The resulting resin was agitated in DCE (25 mL) asBu₄NF.H₂O (0.27 g, 1.05 mmol), TMSN₃ (0.37 mL, 2.8 mmol) and (Ph₃P)₄Pd(20 mol %, 0.08 g, 0.07 mmol) were added. The reaction was agitated atabout rt for about 6 h. The resin was washed with DCE (2×), DMF/H₂O(1:4, 1×), DMF (3×), THF (3×), and ether (1×) to give E4. A portion ofthe resin was cleaved with TFA/DCM (1:1) and the cleaved product wasconfirmed by ES-MS [m/z 312 (MH⁺)].

[0314] Resin E4 was agitated in DMF (25 mL) with DIEA (0.18 mL, 1.05mmol), Fmoc-Phe-OH (0.41 g, 1.05 mmol), HOBT (1.00 mg, cat. amount) andDIC (0.16 mL, 1.05 mmol) for about 18 h. The solution was drawn off andthe resin was washed with DMF (3×), THF (3×), DCM (4×) and ether (1×) toafford E5. A portion of the resin was cleaved with TFA/DCM (1:1) and thecleaved product was confirmed by ES-MS [m/z 681 (MH⁺)].

[0315] The resin E5 was combined with 20% piperidine in DMF (25 mL) andagitated for about 2 h. The solution was drained and the resin waswashed with DMF (3×), THF (3×), and DCM (3×). The resulting resin wasagitated in DMF (25 mL) with DIEA (0.18 mL, 1.05 mmol), Ac-Arg(PMC)—OH(0.51 g, 1.05 mmol), HOBT (1,00 mg, cat. amount), and DIC (0.16 mL, 1.05mmol) overnight. The solution was drawn off and the resin was washedwith DMF (3×), THF (3×), DCM (4×) and ether (1×) to provide E6. Aportion of the resin was cleaved with TFA/DCM (1:1) and the cleavedproduct was confirmed by ES-MS [m/z 923 (MH⁺)].

[0316] The resin E6 was combined with anisole (0.08 mL, 0.70 mmol) inTFA/DCM (1:1, 50 mL) and agitated for 3 h. The solution was drawn offand the resin was washed with fresh 50% TFA/DCM; the filtrates werecombined and evaporated. DCM was added to the remaining residue fourtimes to azetrope off the TFA. The sample was triturated with ether (4×)to give the product Compound 2. ES-MS m/z 657 (MH⁺).

[0317] As a specific embodiment of an oral composition, 100 mg of theCompound 17 of Example 1 is formulated with sufficient finely dividedlactose to provide a total amount of about 580 mg to about 590 mg tofill a size 0 hard gel capsule.

[0318] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

What is claimed is:
 1. A compound of the following formula (I):

wherein A₁, A₂ and A₃ are each independently a D- or L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-₄alkyl), 2,4-diaminobutyricacid (optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl), homoserine(optionally substituted with C₁-C₄alkyl, aryl, or arC₁-C₄alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino,amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl, heteroaryl,arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₁ and R₂ are eachindependently selected from hydrogen, C₁-C₈alkyl, ar(C₁-C₈)alkyl,C₁-C₈alkoxycarbonyl, aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl,C₁-C₈alkylcarbonyl, arylcarbonyl, ar(C₁-C₈)alkylcarbonyl, aminocarbonyl,C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, ar(C₁-C₈)alkylaminocarbonyl,diar(C₁-C₈)alkylaminocarbonyl, heterocyclylcarbonyl,heteroaryl(C₁-C₈)alkyl, heteroaryloxycarbonyl,heteroaryl(C₁-C₈)alkoxycarbonyl, heteroarylcarbonyl,heteroaryl(C₁-C₈)alkylcarbonyl, heteroarylaminocarbonyl,diheteroarylaminocarbonyl, and heteroaryl(C₁-C₈)alkylaminocarbonyl,diheteroaryl(C₁-C₈)alkylaminocarbonyl wherein said aryl, ar(C₁-C₈)alkyl,heteroaryl and heteroaryl(C₁-C₈)alkyl are optionally substituted withone or more of halogen, C₁-C₈alkyl, C₁-C₈alkoxy, hydroxy, cyano, amino,and nitro; R₁ and R₂ are covalently bonded to the N-terminus of A₃ whenp is 1 or A₂ when p is 0; R₃ is selected from hydrogen or C₁-C₈ alkyl;R₄ is selected from unsubstituted or substituted aryl, arC₁-C₈alkyl,C₃-C₈cycloalkyl, heteroaryl, or heteroaryl(C₁-C₈)alkyl, where thesubstituents on the aryl, arC₁-C₈alkyl, cycloalkyl, heteroaryl orheteroaryl(C₁-C₈)alkyl group are independently selected from one or moreof halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈alkyl, C₁-C₈alkoxy,hydroxy, C₁-C₄alkylcarbonyl, C₁-C₈alkoxycarbonyl, fluorinatedC₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl; R₅ isselected from amino, C₁-C₈alkylamino, C₁-C₈dialkylamino, arylamino,arC₁-C₈alkylamino, C₃-C₈cycloalkylamino, heteroalkylC₁-C₈alkylamino,heteroalkylC₁-C₈alkyl-N-methylamino, C₁-C₈dialkylamino(C₁-C₈)alkylamino,—N(C₁-C₈alkyl)-C₁-C₈alkyl-N(C₁-C₈alkyl)₂, —N(C₁-C₈alkyl)(C₁-C₈alkenyl),—N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkylwherein the substituent on the heteroalkyl is selected from oxo, amino,C₁-C₈alkoxy(C₁-C₈)alkyl, C₁-C₈alkylamino or C₁-C₈dialkylamino; X is N orC; Y is N, C or —CO—; provided that when Y is N, then X is C and thereis a double bond between X and Y; provided also that when Y is C, then Xis C and there is a double bond between X and Y; and provided also thatwhen Y is —CO—, then X is N and there is a single bond between X and Y;m is an integer selected from 0, 1, 2 or 3; n is an integer selectedfrom 1 or 2; p is an integer selected from 0 or 1; enantiomers,diastereomers, tautomers, solvates, and pharmaceutically acceptablesalts thereof.
 2. The compound of claim 1, wherein: A₁ is anunsubstituted or substituted L-amino acid selected from the groupconsisting of phenylalanine, cyclohexylalanine, alanine, β-alanine,heteroarylalanine, naphthylalanine, homophenylalanine, arylglycine,heteroarylglycine, aryl-β-alanine, and heteroaryl-β-alanine wherein thesubstituents on the amino acid are independently selected from one ormore of halogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄alkoxycarbonyl,amino, amidino, guanidino, fluorinated C₁-C₄alkyl, fluorinatedC₁-C₄alkoxy, C₁-C₄alkylsulfonyl, C₁-C₄alkylcarbonyl, cyano, aryl,heteroaryl, arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro.
 3. Thecompound of claim 1, wherein: A₂ is an amino acid selected from thegroup consisting of arginine, homoarginine, 2,4-diaminobutyric acidoptionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—), 2,3-diaminopropionic acid (optionally substituted with acyl,C₁-C₄alkyl, aroyl, amidino, or MeC(NH)—), glutamine, and lysine(optionally substituted with acyl, C₁-C₄alkyl, aroyl, amidino, orMeC(NH)—),.
 4. The compound of claim 1, wherein R₁ is hydrogen.
 5. Thecompound of claim 1, wherein: R₂ is selected from hydrogen, C₁-C₈alkyl,aryloxycarbonyl, ar(C₁-C₈)alkoxycarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylcarbonyl, ar(C₁-C₈)alkylcarbonyl, arylaminocarbonyl,diarylaminocarbonyl, C₁-C₈alkylaminocarbonyl, C₁-C₈dialkylaminocarbonyl,ar(C₁-C₈alkoxy)carbonyl, and heterocyclylcarbonyl, wherein said aryl,ar(C₁-C₈)alkyl, heteroaryl and heteroaryl(C₁-C₈)alkyl are optionallysubstituted with one or more of halogen, C₁-C₈alkyl, and C₁-C₈alkoxy. 6.The compound of claim 1, wherein R₃ is hydrogen.
 7. The compound ofclaim 1, wherein: R₄ is substituted aryl, where the substituents on thearyl are independently selected from one to three substituents selectedfrom halogen, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄alkyl, fluorinated C₁-C₄alkoxy or C₁-C₄alkylsulfonyl.8. The compound of claim 1, wherein: R₅ is selected from amino,C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₃-C₈cycloalkylamino, arylamino,arC₁-C₆alkylamino, heteroalkylC₁-C₆alkylamino,—N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂, heteroalkyl or substitutedheteroalkyl wherein the substituent on the heteroalkyl is selected fromoxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl, C₁-C₆alkylamino or C₁-C₆dialkylamino.
 9. The compound of claim 1 wherein: X is C; Y is C; andthere is a double bond between X and Y.
 10. The compound of claim 1wherein: X is C; Y is N; and there is a double bond between X and Y. 11.The compound of claim 1 wherein: X is N; Y is C(O); and there is asingle bond between X and Y.
 12. The compound of claim 1, wherein m isone.
 13. The compound of claim 1, wherein n is one.
 14. The compound ofclaim 1, wherein p is
 0. 15. The compound of claim 1, wherein point ofattachment of -N(R₃)-A₁-A₂—(A₃)_(p)—R₁(R₂) is the 6 position.
 16. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim
 1. 17. A process for making apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier thereby forming a pharmaceuticalcomposition.
 18. A method of treating a condition selected from thegroup consisting of thrombosis, restenosis, hypertension, heart failure,arrhythmia, myocardial infarction, glomerulonephritis, reocclusionfollowing thrombolytic therapy, reocclusion following angioplasty,inflammation, angina, stroke, atherosclerosis, ischemic conditions, avaso-occlusive disorder, neurodegenerative disorders, angiogenesis andrelated disorders and cancer in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thecompound of claim
 1. 19. A method of treating a condition selected fromthe group consisting of thrombosis, restenosis, hypertension, heartfailure, arrhythmia, myocardial infarction, glomerulonephritis,reocclusion following thrombolytic therapy, reocclusion followingangioplasty, inflammation, angina, stroke, atherosclerosis, ischemicconditions, a vaso-occlusive disorder, neurodegenerative disorders,angiogenesis and related disorders and cancer in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the composition of claim
 1. 20. A method ofinhibiting platelet aggregation in a subject in need of treatmentthereof comprising administering to the subject a therapeuticallyeffective amount of the compound of claim
 1. 21. A method of treating acondition mediated by thrombin receptor (PAR-1) in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1.